Dendritic cells (DCs) are antigen-presenting cells of the immune system. They engulf and process bits of bacteria, viruses, and other pathogens before presenting the relevant protein chain targets (antigenic peptides), to Cytotoxic T Lymphocytes (CTL), which recognize and kill virus-infected or cancer cells, and B-lymphocytes, which make antibodies. DCs also engulf cells which are damaged or dead, and are required to induce either a Type 1 response (activation), a Type 2 response (tolerant), or a Type 0 response (neutral). Because the same 20 amino acids make up body parts (self), as well as pathogens (non-self), DCs must evaluate not only the antigen structure, but also the cytokine and other signaling environment present at the time. This multi-layered system is in place to prevent auto-immunity, where the immune system mistakes self for non-self, as well as allergic responses, where a neutral response is required to maintain balance. This complex system of internal checks and balances is exploited by tumor cells, which arise from “self” cells. Tumor cells often secrete factors such as Transforming Growth Factor-beta (TGFβ) which switch responding immune cells toward a TH2-type tolerant response. This allows the tumor cells to grow unchecked, and often aided by, the immune cells. DCs have the capability of programming CD4+ and CD8+ CTL to recognize the MHC (self-protein ID complex) and associated peptide presented. However, the CTL must then decide whether to ignore the cell as self, or initiate lysis, e.g., through the Fas/FasL or Perforin/Granzyme B cell-death systems. The decision will often rely on the activation state of the CTL, the cytokine environment, and the presence or absence of cell-damage factors, e.g., heat-shock proteins, Toll-like receptor activation signals, and the like. During an active pathogen infection, these systems become activated and help steer the CTL response to a Type 1 attack mode.
Immunotherapy, unlike cytotoxic drugs, radiation, and surgery, stimulates the immune system to recognize and kill tumor cells. Numerous attempts have been made in stimulating the immune system to recognize and destroy tumor cells. These have been met with limited success due to the self-identity of peptides selected as target for immunotherapy, lack of immune activation, adverse events, and/or tumor immune evasion mechanisms.
The ability of current cellular therapies, e.g., dendritic cell therapies, to induce durable, complete responses in advanced cancer patients is low (5-10% in the most immunogenic cancer types, lower in others). Often, dendritic cell therapies produce less than desirable results because of low activation (e.g. not enough immune cells to adequately kill all cancer cells), low targeting (e.g., healthy cells are killed and/or tumor cells are not killed), or an immunosuppressed tumor microenvironment, limiting drug efficacy.